Compositions for treatment of ear disorders and methods of use thereof

ABSTRACT

The present invention relates to compositions and methods useful for the treatment of ear disorders, administered to a treated ear in the form of a foam or a mousse. Administering a medicament in such forms will increase the residence time of the medicament in the ear canal, provide relatively uniform distribution of the composition, and can increase the penetration of the active pharmaceutical ingredient in the affected area, may release active substances slowly, enhance treatment effectiveness, increase compliance and is more convenient to use than currently available ear medications. The administration in the form of a foam or a mousse may preferably be provided as a metered dose, of a volume suitable to fill the ear canal.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for thetreatment of ear disorders, wherein the pharmacologically active agentis administered to a treated ear in a form selected from a foam and amousse. The compositions and methods of administering a medicament inthese forms provide accurate dosage volumes, increase the residence timeof the medicament in the ear canal, enhance treatment effectiveness,increase compliance and are more convenient to use than currentlyavailable ear medications.

BACKGROUND OF THE INVENTION Ear Structure

The ear, which is the organ of hearing and balance, consists of theouter, middle, and inner ear. The outer, middle, and inner ear functiontogether to convert sound waves into nerve impulses that travel to thebrain, where they are perceived as sound. The inner ear also helps tomaintain balance.

Outer Ear

The outer ear consists of the external part of the ear (pinna orauricle) and the ear canal (external auditory meatus). The pinnaconsists of cartilage covered by skin and is shaped to capture soundwaves and funnel them through the ear canal to the eardrum (tympanicmembrane), a thin membrane that separates the outer ear from the middleear.

Middle Ear

The middle ear consists of the eardrum and a small air-filled chambercontaining a chain of three tiny bones (ossicles) that connect theeardrum to the inner ear. The ossicles are named for their shapes. Thehammer (malleus) is attached to the eardrum. The Eustachian tube, asmall tube that connects the middle ear with the back of the nose,allows outside air to enter the middle ear. This tube, which opens whena person swallows, helps maintain equal air pressure on both sides ofthe eardrum and prevents fluid from accumulating in the middle ear. Ifair pressure is not equal, the eardrum may bulge or retract, which canbe uncomfortable and distort hearing. The Eustachian tube's connectionwith the middle ear explains why upper respiratory infections (such asthe common cold), which inflame and block the Eustachian tube, can leadto middle ear infections or changes in middle ear pressure, resulting inpain.

Inner Ear

The inner ear (labyrinth) is a complex structure consisting of two majorparts: the cochlea, the organ of hearing; and the vestibular system, theorgan of balance. The vestibular system consists of the saccule and theutricle, which determine position sense, and the semicircular canals,which help maintain balance.

The cochlea, a hollow tube coiled in the shape of a snail's shell, isfilled with fluid. Within the cochlea is the organ of Corti, whichconsists, in part, of about 20,000 specialized cells, called hair cells.These cells have small hairlike projections (cilia) that extend into thefluid. Sound vibrations transmitted from the ossicles in the middle earto the oval window in the inner ear cause the fluid and cilia tovibrate. Hair cells in different parts of the cochlea vibrate inresponse to different sound frequencies and convert the vibrations intonerve impulses. The nerve impulses are transmitted along fibers of thecochlear nerve to the brain. Despite the protective effect of theacoustic reflex, loud noise can damage and destroy hair cells. Once ahair cell is destroyed, it does not appear to regrow. Continued exposureto loud noise causes progressive damage, eventually resulting in hearingloss and sometimes noise or ringing in the ears (tinnitus). Thesemicircular canals are three fluid-filled tubes at right angles to oneanother. The canals contain hair cells that respond to the movement ofthe fluid. If the semicircular canals malfunction, as may occur in anupper respiratory infection and other conditions both temporary andpermanent, a person's sense of balance may be lost or a whirlingsensation (vertigo) may develop.

Use of Ear Drops for the Treatment of Ear Disorders

Currently, ear care products (otic, ototopical agents) are administeredto the treated subject in the form of drops. Generally, ear drops arebased on antibiotic agents, antibacterial agents, antifungal agents,antiviral agents, steroid derivatives, anti-inflammatory agents,analgesic compounds or a mixture thereof. For example, initial therapyfor acute otitis externa (AOE) is typically a combination consisting ofneomycin, polymyxin B and a steroid (commercially available as forexample, Cortisporin™) (Lee L, Steinberg I, Gill M A. Management of EarInfections. Cal Parma 2001; Spring; 56-64). Current medications alsoinclude quinolone derivatives i.e. Ciprofloxacin 1% or Oflaxacin 0.3%.Other compositions of ear drops are further described in U.S. Pat. Nos.5,401,741; 5,679,665; 5,965,549; and 5,843,930 the entire disclosures ofwhich are hereby incorporated by reference.

Another common use of ear drops is for ear pain treatment. Ear pain(otalgia) can range from mild discomfort or a feeling of fullness tosevere intense pain, and can be very unpleasant and even unbearable,especially in children. Usually, ear pain results from pathologicalconditions of the external or middle ear. Such pathological conditions,discussed lengthily above, may be caused by infection, trauma, orblockage of the ear. Briefly, common trauma may result by use of acotton swab to clean the ear or as a result of sudden changes inpressure such as changes in altitude when flying or diving. Blockage ofthe ear canal can be caused by excessive earwax (cerumen) or foreignobjects such as beads, beans or bugs. Infections of the ears includeotitis externa (swimmer's ear), otitis media, an infection of the innerear, mastoiditis and other pathologies as mentioned above and fullydescribed in the literature. Other disorders that may cause ear pain areallergic reactions, ruptured eardrum, acute sinusitis, chronicsinusitis, tooth abscess, sore throat with referred pain to the ears,Meniere's disease, tumors of the ear, which may be cancerous or benignand temporomandibular joint (jaw) syndrome.

Currently available analgesic ear drops used for the treatment of earpain usually contain an analgesic compound such as: benzocaine,tetracaine, amethocaine antipyrine and/or phenazone.

Ear drops are usually administered to the treated ear by tilting thehead of a treated subject to the side, instilling drops of themedicament into the ear and maintaining the adopted position for fewminutes, in order to allow the medicine to reach the interior of theear. A clean cotton-wool plug may be inserted into the opening of theear to prevent the medication from leaking out. In addition, in order toprevent contamination of the ear drops, the bottle tip must not be incontact with any surface, including the hands and the ear itself.

A number of drawbacks are associated with ototopical administration inthe form of drops. In principle, ear drops exert their effect by directcontact with the affected area. If administration is poor (e.g., thehead of the treated subject is not tilted long enough) and the dropscannot reach the infected area, the active agent cannot be effective.Delivery can be impaired in a number of different ways, includingfailure of the drops to enter the ear canal, short contact period of themedicament with the ear canal since the drops are naturally washed outor because the head of the treated subject is not tilted long enough forthe agent to reach its target. In addition, the form of the currentmedicaments as ear drops is difficult to apply, especially to smallchildren and animals that tend not to cooperate mainly due to thedifficulty in maintaining a sedentary position for a prolonged period(several minutes). Cotton wool, that is usually added to the ear afteradministering the drops, might be pushed inside the ear canal and isdifficult to remove. Also, the existing drugs often inadequately addressa patient's needs for efficacy and aesthetics (e.g. running of drops onface and neck), and the failure to address those needs may decreasepatient compliance and impair overall treatment.

Attempts have been made to provide alternate devices and methods fordelivery of medication to the ear canal. U.S. Pat. No. 6,764,470 teachesan ear plug medication administration device that maintains themedication in the ear canal. The device comprises a resilient casingcomprising a barrier defining an enclosed reservoir for a medication.The casing is configured to be compressed to fit within the ear, andconfigured to eject the medication upon being compressed. This devicerequires considerable handling and is awkward for use with infants andchildren.

U.S. Pat. No. 4,241,048 discloses anesthetic compositions comprising atherapeutically effective amount of powdered Benzocaine. In particularembodiments, the composition is in the form of a foamable liquid,aerosol product or a solid. In the disclosure, it is noted that thecompositions “.can also be applied to burns, sunburn, poison ivy, insectbite, otic (ear), teething (gums) preparations, etc.”

US patent application publication number 20020064541, and U.S. Pat. Nos.5,744,166 6,238,650 are directed to compositions for topical applicationin the form of microcapsules or microspheres.

The above disclosures neither teach nor suggest a composition or use ofa foam or mousse to treat ear disorders.

Foam Delivery of Therapeutic Agents

Various foams useful for the delivery of therapeutic agents to the skinand body cavities are taught in the art. U.S. Pat. No. 6,730,288discloses aerosol foam, also referred to as “mousse”, for topicaladministration of insoluble pharmaceutically active ingredients. Thecomposition comprises an occlusive agent in an amount sufficient to forman occlusive layer on the skin. Administration of mousse to the ear isneither taught nor suggested.

International patent application publication WO 2004/037225 teachesalcohol-free cosmetic or pharmaceutical foams suitable for delivery ofboth water soluble and oil-soluble pharmaceutical agents. That patentteaches foams useful for topical application of pharmaceutical agents tobody cavities.

U.S. Pat. No. 4,915,934 teaches a quick-breaking foamable biocidalcomposition, comprising a quick breaking alcoholic foaming agentcomprising: an aliphatic alcohol, a fatty alcohol, water and asurface-active agent.

U.S. Pat. No. 5,759,520 discloses a method for treating conditions ofthe gastro-intestinal tract, comprising administering from a pressurizedcontainer an aqueous foamable composition comprising a major amount byweight of water; a foaming agent consisting of a water-immiscibleliquified gas; at least one emulsifying surfactant; Xanthan gum; and aneffective amount of a pharmaceutically active substance; the compositionhaving a delayed foaming action.

U.S. Pat. No. 6,126,920 teaches methods of treating various skindiseases, including scalp psoriasis, utilizing a foamable pharmaceuticalcomposition comprising a corticosteroid active substance, a quick-breakfoaming agent, a propellant and a buffering agent. The present inventionis preferably intended to increase the residence time of apharmaceutical composition in the ear, and does not preferentially usequick breaking foams.

U.S. Pat. Nos. 5,393,528 and 5,529,782 teach a device comprising adissolvable film made of polyvinyl alcohol, polyethylene oxide,hydroxypropylmethyl cellulose and mixtures thereof and a method for thedelivery of medication. Nitrogen gas may be introduced while mixing toform frothy foam. Those patents do not disclose administration of foaminto a bodily cavity.

UK Patent GB0933486 teaches liquid non-aqueous foamable aerosolcompositions and provides a general disclosure of stable foams. Thatdisclosure mentions in passing that “a quick breaking foam may berequired for applying a uniform coating of a non-aqueous liquid to anirregular or inaccessible surface such as the middle ear” but neitherteaches nor suggests compositions for the treatment of ear disorders ormethods of administering a composition to the outer ear, which is themore appropriate method of application.

U.S. Pat. No. 6,521,213 teaches a method for preventing otitis externaby administering an aerosolized mixture of lipid crystals to theepithelial lining of the external auditory canal. The patent furtherteaches a method of treating otitis externa by administering a mixtureof lipid crystals further comprising a therapeutic agent. The presentinvention does not use lipid crystals.

U.S. Pat. No. 4,305,936 relates to a composition comprising at least onecorticosteroid, for topical or local application to the skin or bodycavity. According to one embodiment of that patent, the preparation canproduce a foam when packaged in the form of an aerosol or non-aerosolfoam-forming closure system.

None of the above disclosures teach or suggest the delivery ofmedicaments specifically to the ear in the form of a foam or mousse.

Thus, there is a widely recognized need for, and it would be highlyadvantageous to have convenient and practical forms of medicaments totreat ear disorders, that ma overcome all drawbacks related to the useof such medicaments in the form of drops.

SUMMARY OF THE INVENTION

The present invention provides novel delivery systems for providing amedicament for the treatment of ear disorders in general, and of outerear and middle ear disorders in particular. Specifically, the presentinvention provides compositions and methods for treatment of an eardisorder in a subject, the methods comprising administering apharmaceutical composition in the form of a foam or mousse through theexternal auditory meatus (EAM) of the subject.

According to the principles of the present invention the formulation andadministration of such a medicament into the ear is in a form selectedfrom a foam or mousse.

The application of a medicament in these forms allows prolonged contactof the active agent/s with the surface of the ear canal, and thereforeenables non-frequent applications (e.g. once or twice a day only). Theprolonged contact of the active agent/s with the affected area furtherfacilitates rapid healing compared to the conventional treatment withear drops. Furthermore, administration of such forms into the ear ismuch more convenient than the administration of drops or insertion of adevice, and makes it completely unnecessary either to tilt the head of atreated subject to the side during administration of the medicament, orto plug the ear meatus with a cotton-wool or other plug, in order toprevent the medication from leaking out. Additionally, administration offoam or mousse into the ear may be used to provide a measured dose ofmedicament to the ear.

In one aspect the present invention provides a pharmaceuticalcomposition for the treatment of an ear disorder in a form selected fromfoam and mousse comprising:

a) at least one pharmaceutical agent known to affect an ear disorder;

b) a pharmaceutically acceptable carrier comprising at least onedispersing agent that is a foam forming agent; and

c) a dispensing device adapted for the dispensing the pharmaceuticalagent of a) admixed with the agent of b) to the external auditory meatusin a form selected from a foam and a mousse.

In certain embodiments the dispersing agent that is a foam forming agentis selected from a surfactant, a cholesteryl ester, a fatty acid, aphospholipid, a carbohydrate and a protein.

In certain embodiments the pharmaceutical composition is provided as anaerosol foam or mousse and the composition further comprises apropellant. The propellant used may be chosen from conventional aerosolpropellants. Thus, the propellant may be selected from propane, butane,dichloro difluoro methane, dichloro tetrafluoro ethane, octafluorocyclobutane, and mixtures of two or more thereof. The propellant may bepresent in amounts of about 3 to about 30% w/w.

In other embodiments the composition is provided as non-aerosol foam ormousse.

In certain embodiments of the present invention, the pharmaceuticalcomposition is administered to the treated subject in a dispensingdevice that provides a metered dose and an otic adaptor adapted toadminister the composition at or through the external auditory meatus.Preferably each metered dose of the composition provides an acceptabletherapeutic dose in a final volume, which is suitable to fill theexternal auditory canal of the treated subject.

In some embodiments the ear disorder is selected from an external eardisorder, a middle ear disorder and an inner ear disorder. In otherembodiments the external ear disorder or diseases is selected from thoseresulting from infection, allergy, trauma and cysts and tumors andinclude in a non-limiting manner otitis externa (“Swimmer's Ear”),necrotizing external otitis, otomycosis, perichondritis, bullousmyringitis, herpes zoster oticus (Ramsey Hunt Syndrome), contactdermatitis, ear eczema, lacerations of the external canal, presence offoreign bodies, pilar (sebaceous) cysts, epidermal cysts, benign lesionsincluding exostosis and malignant lesions including basal cellepithelioma and squamous cell carcinoma. According to specificembodiments the external ear disorder is selected from otitis externa,acute otitis externa and suppurative otitis externa.

In other embodiments the middle ear disorder and disease is selectedfrom those resulting from infection, trauma and tumors including otitismedia, chronic otitis media, serous otitis media (otitis media witheffusion) acute and chronic suppurative otitis media, acute and chronicmastoiditis, adenoid hypertrophy, neoplasia, intratubal obstruction,middle ear obstruction, perforation of the eardrum (tympanic membrane),cholesteatoma (congenital, primary acquired, secondary acquired),tympanosclerosis, temporal bone fractures, barotrauma, glomus tumors andmalignant neoplasia including squamous cell carcinoma. In one embodimentthe ear disorder is a middle ear disorder selected from acute otitismedia, suppurative otitis media and mastoiditis.

In specific embodiments the symptoms of middle ear pathology areselected from otalgia, tinnitus, and hearing loss. The etiology may be adirect disorder or disease of the middle ear or may result from referredpain.

In other embodiments the disorders and diseases of the ear are selectedfrom otalgia caused by any physical or biological cause includingwithout limiting: blockages, barotraumas, allergic reactions, acutesinusitis, chronic sinusitis, tooth abscess, sore throat with referredpain to the ears, Meniere's disease, myringitis, tumors,temporomandibular joint syndrome, temporal bone fracture and any othercondition that requires administration of any kind of medicament intothe ear canal of a treated subject in particular.

In some embodiments the ear disease or disorder is an inner ear disorderincluding symptoms of Meniere's disease, which may be treated byadministering the composition of the present invention to the externaland middle ear.

In specific embodiments the ear disorder is selected from an earinfection, an ear tumor and otalgia (ear pain).

In specific embodiments the ear disorder is otalgia, the otalgia causedby any physical, chemical or biological cause. In one embodiment thecause of otalgia is selected from a blockage, an external ear infection,a middle ear infection, an allergic reaction, a tooth abscess and anupper respiratory infection.

In certain embodiments of the current invention the pharmaceuticalcomposition comprises a therapeutically effective amount of at least oneof the following pharmaceutical agents selected from an antibacterialagent, an antibiotic agent, an anti-fungal agent, an anti-viral agent, asteroid, an anti-inflammatory agent and an analgetic agent or a mixturethereof of at least two of such agents.

In one embodiment of the invention, the pharmaceutically active agent isan antibiotic agent. The antibiotic agent may be, for example, amikacin,gentamycin, tobramycin, streptomycin, netilmycin, kanamycinciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin,levofloxacin, enoxacin, sulfonamides, polymyxin, chloramphenicol,neomycin, paramomomycin, colistimethate, bacitracin, vancomycin,tetracyclines, rifampins, cycloserine, beta-lactams, cephalosporins, andpharmaceutically acceptable derivatives thereof. In specific embodimentsthe pharmaceutical agent is an antibiotic selected from neomycin,ofloxacin and ciprofloxacin.

In some embodiments the pharmaceutically active agent is anantibacterial agent selected from zinc, acetic acid or boric acid or amixture thereof.

In certain embodiments the pharmaceutically active agent is ananti-inflammatory agent selected from a non-steroidal anti-inflammatorydrug (NSAID) and a steroid. The steroid may be selected from the groupconsisting of betamethasone, betamethasone dipropionate, fluocinonide,fluocinoline acetonide, hydrocortisone, methylprednisolone, clobetasol,beclomethasone, dexamethasone sodium phosphate, triamcinolone andpharmaceutically acceptable derivatives thereof. In specific embodimentsthe steroid is selected from hydrocortisone, betamethasone anddexamethasone.

In some embodiments the pharmaceutically active agent is an antifungalagent selected from the group consisting of amphotericins, fluconazole,flucytosine, natamycin, miconazole, ketoconazole, amphotericin B,nystatin, cromolyn, lodoxamide, levocabastine, naphazolin, antazoline,pheniramimane and pharmaceutically acceptable derivatives thereof.

In some embodiments the pharmaceutically active agent is a localanesthetic agent selected from the group consisting of benzocaine,benzyl benzoate, bupivacaine, calamine, chloroprocaine, chloroxylenol,cinchocaine, cocaine, dexivacaine, diamocaine, dibucaine, dyclonine,etidocaine, hexylcaine, ketamine, levobupivacaine, lidocaine, menthol,mepivacaine, oxethazaine, phenol, pramoxine, prilocalne, amethocaine,tetracaine, proparacaine, propoxycaine, pyrrocaine, resorcinol,risocaine, rodocaine, ropivacaine, tetracaine, and pharmaceuticallyacceptable derivatives thereof. In specific embodiments thepharmaceutical agent is an analgetic selected from anti-pyrine,lidocaine and derivatives thereof.

In certain embodiments the pharmaceutical composition comprises morethan one pharmaceutically active agent. In specific embodiments themedicament comprises neomycin, polymyxin B and hydrocortisone. In otherembodiments the pharmaceutical composition comprises chloroxylenol(halogenated phenol), pramoxine hydrochloride and hydrocortisone.

It is explicitly understood that the pharmaceutical composition andmethods of the present invention are suitable for pharmacologicallyactive agents, whether water soluble, poorly water soluble or waterinsoluble. In certain embodiments the pharmaceutically active agent isneither soluble in aqueous carriers nor in a lipid carrier. Thejudicious choice of ingredients will allow foam delivery whether theactive ingredients are water-soluble or not. Combinations of activeingredients that are individually and independently water soluble orinsoluble may also be practiced according to the present invention.There are many available solutions to the problem of formulation ofpoorly soluble ingredients for improved drug bioavailability includingthe use of surfactants, micelle solutions, emulsions, microemulsions andorganic cosolvents, as are well known in the art of pharmaceuticalformulations.

In some embodiments the pharmaceutically acceptable carrier is ahydrophilic carrier. In certain embodiments the composition of thepresent invention is an aqueous based foam. In some embodiments thecomposition comprises an oil-in-water emulsion, or microemulsion.

In other some embodiments the pharmaceutically acceptable carrier is alipophilic carrier. In certain embodiments the composition is alipid-based mousse. In some embodiments the composition comprises awater-in-oil emulsion.

According to various embodiments the at least one dispersing agent thatis a foam forming agent is selected from the group consisting of naturalor synthetic agents including a surfactant, a cholesteryl esters, afatty acid, a phospholipid, a carbohydrate, and a protein. In certainembodiments the pharmaceutically acceptable carrier further comprises atleast one surfactant selected from a natural or synthetic ionic ornon-ionic surfactant or mixture thereof.

The pharmaceutical composition provided by the present invention, may beadministered to the ear of the treated subject through a device in whichthe compositions are packed under pressure, suitable for application tothe treated are in a form selected from a foam or mousse. In onepreferred embodiment the dispensing device is selected from an aerosoldispensing device and a non-aerosol dispensing device. According toanother aspect the present invention provides a device or apparatus foradministration of a medicament to the ear of a subject in the form of afoam or mousse comprising a container comprising the pharmaceuticalcomposition and an extension, typically a tube extending therefrom, saidextension adapted to access the outer ear in a convenient and gentlemanner. Preferably, the medicament is formulated as a foamablecomposition, which, upon admixing with a gas propellant in an aerosolcontainer, produces a foamable composition that is suitable foradministration to the external auditory meatus (ear canal).Alternatively the foamable composition is administered using anon-aerosol dispenser.

According to another aspect the present invention provides a method forthe treatment of an ear disorder in a subject in need thereof comprisingadministering an amount of a pharmaceutical composition in a formselected from foam and mousse through the external auditory meatus ofsaid subject so as to thereby treat the ear disorder.

In another aspect the present invention further provides a method ofpreparing a pharmaceutical composition for the treatment of an eardisorder in the form selected from a foam and a mousse, the methodcomprising the steps of:

a) providing a pharmaceutical agent known to affect an ear disorder;

b) admixing the pharmaceutical agent of step (a) with a suitablepharmaceutically acceptable carrier comprising at least one dispersingagent that is a foam forming agent; and

c) introducing the mixture of (b) into a dispensing device adapted forthe dispensing the composition to the external auditory meatus in theform selected from a foam or mousse.

In yet another aspect the present invention provides a method for thetreatment of an ear disorder in a subject in need of such treatment, themethod comprising the steps of:

a) providing a pharmaceutical agent known to affect an ear disorder;

b) admixing the pharmaceutical agent of step (a) together with apharmaceutically acceptable carrier comprising at least one dispersingagent that is a foam forming agent;

c) introducing the mixture formulation of step (b) in a container thatenables the dispersion of said mixture in a form selected from foam andmousse; and

d) administering the formulation of step (c) to the external auditorymeatus of said subject so as to thereby treat the ear disorder.

In one preferred embodiment of the invention, the pharmaceuticalcomposition is administered to the treated subject in a dispensingdevice that provides a metered dose. Preferably each metered dose of theformulation provides an acceptable therapeutic dosage in a final volume,which is suitable to fill the ear canal of the treated subject.

The present invention further provides use of a pharmaceuticalcomposition in a form selected from a foam and a mousse for thetreatment of any ear disorder which requires administration of apharmaceutical composition through the external auditory meatus of atreated subject, so as to thereby treat the ear disorder.

In specific embodiments the treated subject is a mammal, preferably ahuman. In other embodiments the mammal is a domestic animal.

These and further features of the present invention will be betterunderstood in conjunction with the drawings, detailed description,examples and claims that follow.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 represents a side view of one embodiment of the delivery of thepharmaceutical composition of the invention in the form of a foam ormousse to the ear canal. The figure is labeled as follows: (1) markspart of the outer ear, the auricle; (2) identifies the ear canal(external auditory meatus); (3) identifies the ear drum (tympanicmembrane).

FIG. 2 represents a side view of one embodiment of a delivery device forproviding a metered dose of a pharmaceutical composition of theinvention. (1) marks part of the outer ear, the auricle; (2) illustratesa metered dose of foam or mousse following administration into the earcanal (external auditory meatus); (3) identifies the ear drum (tympanicmembrane).

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, ear care medicaments in afoam-based formulation are provided. More specifically, the presentinvention provides a method for the treatment of ear disorder in asubject in need of such treatment comprising administering an amount ofa pharmaceutical composition in a form of foam through the externalauditory meatus of said subject so as to thereby treat the subject.

As used herein, the term “foam” or “mousse” is defined any lightweightmaterial in cellular form which is made by introducing gas bubbles intoa liquid phase.

As used herein, the term “foam forming agent” is meant to include foamproducing agents and compounds that are able to generate a foamablecomposition when admixed with a liquid or gel composition. The foamablecomposition generates a foam within the dispensing device or upondispensing from the dispensing device. In certain embodiments thepresent invention provides a stable foam, i.e. wherein breaking of thefoam is delayed.

The foam base formulations as opposed to ear drops offer an improvedcompliancy, i.e. the foam form could be applied infrequently to thetreated area (e.g. once/twice daily) instead of frequent applications ofcurrent available ear drops (2-6 times a day). The foam-basedformulation provides an improved administration to the treated subject,especially to infants, children and animals, since foam does not requirespecial position, such as head tilting for several minutes. Furthermore,formulation in the form of a foam enable improved delivery of themedicament, so as the foam evaporates spontaneously after pre-determinedperiod of time (by formulation), out of the ear without dripping. Inaddition, when the foam is applied to the ear, it does not leave anyresidue, stains or odor after it dries. Moreover, the uniqueness of thefoam formulation is that there is a relatively uniform concentration ofactive ingredients at every site of the foam surface; hence the contactarea of the active ingredient within the ear canal is effectivelyincreased. The foam formulation further enables the active therapeuticagent/s to contact rapidly the treated area with substantially 100%coverage, and can improve penetration into the affected area.

Among other advantages, use of a foam-based formulation avoids the needand dangers of a cotton plug or wick, thus it dispenses with the use ofsuch cotton, which is uncomfortable and may lead to deep insertion ofthe cotton, and the need for a trained physician to pull it out. Anotheradvantage is in the metered, or measured, dosing accompanied by thedelivery device. A premeasured dose obviates the uncertaintiesassociated with delivering the correct amount of medicament.

In one aspect the present invention provides a pharmaceuticalcomposition for the treatment of an ear disorder in a form selected fromfoam and mousse comprising:

a. at least one pharmaceutical agent known to affect an ear disorder;

b. a pharmaceutically acceptable carrier comprising at least one foamforming agent;

c. a dispensing device adapted for the dispensing the agent of a) withthe agent of b) to the external auditory meatus.

In one embodiment of the invention, the treated ear disorder is anycondition that requires administration of any pharmaceutical compositioninto the ear canal of the treated subject, so as to thereby treat theear disorder. Such conditions include without limiting otitis externa,including acute otitis externa, acute otitis media, chronic suppurativeotitis media, infections of the inner ear, mastoiditis, perforation ofthe tympanic membrane, ruptured eardrum, otalgia caused by any physicalor biological cause as detailed previously including without limiting:allergic reactions, acute sinusitis, chronic sinusitis, tooth abscess,sore throat with referred pain to the ears, Meniere's disease, tumorsand temporomandibular joint syndrome.

In another embodiment, the pharmaceutical composition of the presentinvention is used to manufacture a medicament for the treatment of eardisorders, which is administered to the subject in need of suchtreatment in the form of foam or mousse.

Pharmaceutical Agents

In a further embodiment, the pharmaceutical composition of the presentinvention comprises at least one therapeutically active pharmaceuticalagent.

As used herein, the term “pharmaceutical composition” or “medicament or“therapeutically active agent” or “active agent” or “agent”, are allbroadly used to mean any chemical or material that is desired to beapplied, administered or used to treat ear disorders and can include, byway of illustration and not limitation, any substance which is capableof altering a biologic, physiologic and/or immunologic function, andalso substances generally referred to as pharmacological agents anddrugs, including antibiotic agents, antibacterial agents, antifungalagents, steroid agents, anti-inflammatory agents and local anestheticagents. The invention is meant to include a pharmaceutical compositioncomprising at least one therapeutically active agent.

In one embodiment of the invention, the therapeutically active agent isan antibiotic agent. The antibiotic agent may be, for example, neomycin,amikacin, gentamycin, tobramycin, streptomycin, netilmycin, kanamycinciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin,levofloxacin, enoxacin, sulfonamides, polymyxin, chloramphenicol,neomycin, paramomomycin, colistimethate, bacitracin, vancomycin,tetracyclines, rifampins, cycloserine, beta-lactams, cephalosporins, andpharmaceutically acceptable derivatives thereof. In specific embodimentsthe pharmaceutical agent is an antibiotic selected from neomycin,ofloxacin and ciprofloxacin.

In a different embodiment, the active agent used in the provided methodis an antibacterial or bacteriostatic agent. Such antibacterial agentmay be, for example, zinc, acetic acid or boric acid or a mixturethereof.

In yet, a different embodiment of the present invention, the activeagent is a steroid or steroid derivative. Such a steroid includeswithout limiting betamethasone, betamethasone dipropionate,fluocinonide, fluocinoline acetonide, hydrocortisone,methylprednisolone, clobetasol, beclomethasone, dexamethasone sodiumphosphate, triamcinolone and pharmaceutically acceptable derivativesthereof.

In one another embodiment, the therapeutically active agent is anantifungal agent. The antifungal agent may be selected from the groupconsisting of amphotericins, fluconazole, flucytosine, natamycin,miconazole, ketoconazole, amphotericin B, nystatin, cromolyn,lodoxamide, levocabastin, naphazolin, antazoline, pheniramine andpharmaceutically acceptable derivatives thereof.

In a further embodiment, the therapeutically active agent is ananti-inflammatory agent. Such an agent may be, for example, anynon-steroidal anti-inflammatory agent (NSAID), antipyrin andpharmaceutically acceptable derivatives thereof. Examples of thenon-steroidal anti-inflammatory drug (NSAID) which is advantageouslyadministered by the formulations of this invention include salicylicacid derivatives, such as, for example, aspirin; heteroaryl aceticacids, such as, for example, tolmetin, diclofenac, ketorolac;arylpropionic acids, such as, for example, ibuprofen, naproxen,flurbiprofen, ketoprofen, fenoprofen, oxaprozin; anthranilic acids(fenamates), such as, for example, mefenamic acid, meclofenamic acid,flufenamic acid; enolic acids, such as, for example, oxicams (e.g.,piroxicam, tenoxicam), pyrazolidinediones (e.g., phenylbutazone,oxyphenthatrazone); alkanones, such as, for example, nabumetone. Amongthese, especially preferred, based on the current level of knowledge inthe pharmacological arts, are ibuprofen, diclofenac, ketorolac,naproxen, flurbiprofen, ketoprofen and piroxicam. More generally,however, any of the government approved NSAIDs, such as listed in, forexample, the most current edition of The Merck Index, may beadvantageously used.

In still, another embodiment of the invention, the active agent is alocal anesthetic agent. Such agent may be selected, for example, fromthe group consisting of benzocaine, benzyl benzoate, bupivacaine,calamine, chloroprocaine, chloroxylenol, cinchocaine, cocaine,dexivacaine, diamocaine, dibucaine, dyclonine, etidocaine, hexylcaine,ketamine, levobupivacaine, lidocaine, menthol, mepivacaine, oxethazaine,phenol, pramoxine, prilocalne, amethocaine, tetracaine, proparacaine,propoxycaine, pyrrocaine, resorcinol, risocaine, rodocaine, ropivacaine,tetracaine, and pharmaceutically acceptable derivatives thereof.Compositions according to the present invention may comprise anyconventional carriers, excipients or adjuvant used in pharmaceuticals,personal care formulations and compositions or veterinary formulations.These carriers, excipients and adjuvants include, but are not limited tothe following:

Acidifying agents, such as, boric acid, acetic acid, glacial aceticacid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloricacid, malic acid, nitric acid, phosphoric acid, sulfuric acid andtartaric acid.

Alcohol denaturants, such as, denatonium benzoate, methyl isobutylketone and sucrose octacetate.

Alkalizing agents including ammonia solution, ammonium carbonate,diethanolamine, diisopropanolamine, potassium hydroxide, sodiumbicarbonate, sodium borate, sodium carbonate, sodium hydroxide ortrolamine.

Antimicrobial preservatives, such as, benzalkonium chloride,benzalkonium chloride solution, benzelthonium chloride, benzoic acid,benzyl alcohol, butylparaben, acetylpyridinium chloride, chlorobutanol,chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben,methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuricacetate, phenylmercuric nitrate, potassium benzoate, potassium sorbate,propylparaben, propylparaben sodium, sodium benzoate, sodiumdehydroacetate, sodium propionate, sorbic acid, thimerosal and thymol.

Antioxidants, such as, ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, hypophosphorous acid,monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium thiosulfate, sulfur dioxide, alphatocopherol and other tocopherols and tocopherol derivatives.

Buffering Agents, including acetic acid, ammonium carbonate, ammoniumphosphate, boric acid, citric acid, lactic acid, phosphoric acid,potassium citrate, potassium metaphosphate, potassium phosphatemonobasic, sodium acetate, sodium citrate, sodium lactate solution,dibasic sodium phosphate and monobasic sodium phosphate.

Ointment Bases, including lanolin, anhydrous lanolin, hydrophilicointment, white ointment, yellow ointment, polyethylene glycol ointment,petrolatum, hydrophilic petrolatum, white petrolatum, rose waterointment and squalane.

Plasticizers, e.g. castor oil, diacetylated monoglycerides, diethylphthalate, glycerin, mono- and di-acetylated monoglycerides,polyethylene glycol, propylene glycol, triacetin and triethyl citrate.

Solvents, for example, acetone, alcohol, diluted alcohol, amylenehydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride,chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexyleneglycol, isopropyl alcohol, methyl alcohol, methylene chloride, methylisobutyl ketone, mineral oil, peanut oil, polyethylene glycol, propylenecarbonate, propylene glycol, sesame oil, water for injection, sterilewater for injection, sterile water for irrigation and purified water.

Sorbents, such as, powdered cellulose, charcoal, purified siliceousearth or carbon dioxide sorbents (e.g. barium hydroxide lime, sodalime).

Stiffening Agents, for example, hydrogenated castor oil, cetostearylalcohol, cetyl alcohol, cetyl esters wax, hard fat, paraffin wax,polyethylene excipient, stearyl alcohol, emulsifying wax, white wax andyellow wax.

Suspending and/or Viscosity-increasing agents and adjuvants for afoamable liquid or gel base including, acacia, agar, alginic acid,aluminum monostearate, bentonite, purified bentonite, magma bentonite,carbomer 940 or 980, carboxymethylcellulose calcium,carboxymethylcellulose sodium, carboxymethycellulose sodium 12,carrageenan, microcrystalline and carboxymethylcellulose sodiumcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, polyoxyethylene-polyoxypropylene-blockpolymers, hydroxypropyl methylcellulose, magnesium aluminum silicate,methylcellulose, pectin, polyethylene oxide, polyethylene glycol, woodwax, alcohols, polyvinyl alcohol, povidone, propylene glycol alginate,silicon dioxide, colloidal silicon dioxide, sodium alginate, tragacanthand xanthan gum, cocoa butter, hard fat and polyethylene glycol.

Agents that promote penetration, including urea, non-ionic detergentse.g. NP-40, Triton X-100, ionic detergents such as sodium dodecylsulphate, lauryl decyl sulphate and chaotrophic salts.

Foam and Mousse Compositions

The pharmaceutical compositions of the present invention, as well asmedicaments prepared by using these compositions may be altered into theform of a foam or mousse by any method known in the art for producingfoam or mousse. For detailed description of such methods see forexample: US Patent applications 20040057922; 20020018812 and U.S. Pat.Nos. 6,730,288; 5,369,131, International patent application publicationWO 2004/037225 all incorporated herein by reference. In some embodimentsthe foamable composition, when placed in an aerosol container andcombined with a liquefied gas propellant, releases a therapeuticallybeneficial foam or mousse product. In other embodiments the compositionmay be formulated as non-aerosol foam, for example in a propellant freedispenser.

The pharmaceutical compositions provided by the present invention, maybe administered to the ear of the treated subject through a device inwhich the compositions would be packed under pressure, prepared to beapplied to the treated object in a form of foam, through an extension,nozzle or tube, said extension adjusted to access the outer ear in aneasy and user friendly manner (FIGS. 1 and 2).

In one embodiment, the foam is ejected through an actuator that iselongated a few centimeters with a narrow stem-like part, which ends ina rounded and wider orifice, which prevents entry into and injury of theear canal. In light of the wider and rounded tip of the stem, it isdifficult, if not impossible to insert it deep into the ear canal. Whenthe foam is ejected into the ear canal it expands and fills the wholeear canal, therefore it contacts with the whole ear canal area. This hasmany advantages since it enables contact of the active compound(pharmaceutical) for extended periods of time with the walls of the earcanal and therefore exerts its effect. FIGS. 1 and 2 illustratenon-limiting example of a device for the administration of thecomposition of the present invention. In FIG. 1, the parts of the earare as follows: (1) markes part of the outer ear (auricle); (2)identifies the ear canal (external auditory meatus); (3) identifies theeardrum (tympanic membrane).

According to one preferred embodiment the foam is ejected from adispensing device in a measured or metered amount. A metered dose isillustrated in FIG. 2. In FIG. 2, (2) illustrates a non-limiting exampleof a measured dose of foam or mousse in the ear canal, followingadministration.

In one another embodiment, the device is an aerosol device. As usedherein, the term “aerosol” is directed to a container that contains aliquid with gas under pressure for dispensing said liquid as foam. Theuse of aerosol device is well known in the art to produce foam. Anaerosol dispensing device is composed of a standard aerosol can (such asaluminum or tinplate), which can contain pressure higher than theatmospheric pressure. In the aerosol there is usually a liquid or gel inmono-phasic solution (i.e. homogeneous solution) or in bi-phasicsolution (i.e. aqueous solution and oil solution). The container istightly closed with a valve orifice. Thereafter a propellant (i.e. aliquefied gas) such as butane, propane or any other propellant as isknown in the art is inserted, which creates the pressure inside thecontainer. The way in which a product is dispensed as foam (mousse orgel) is directly influenced by the mixture of the product solution,propellant type and the technical design of the aerosol valve andactuator. Inside the container there is high pressure, (e.g. 3atmospheres), and when the container is shaken, even minimally, the gasand liquid or liquids are mixed. Further description of aerosol devicesand the creation of foam and dispersion processes are disclosed by wayof example in U.S. Pat. Nos. 5,322,683; 5,397,564; and 6,730,288 all ofwhich incorporated herein by reference.

In other embodiments the composition is administered as a foam or mousseusing a non-aerosol device. Non-aerosol may be advantageous for certaincompositions and non-aerosol dispensers are known in the art asdisclosed by way of example in U.S. Pat. Nos. 5,635,469; 6,612,468;6,660,282; and 6,030,931 all of which incorporated herein by reference.

U.S. Pat. No. 6,030,931 describes a non-aerosol pump foaming compositionfree of water insoluble emollients. Transparent systems achieve aluxurious foam generated through use of select amphoteric surfactantsand densifying agents. Another non-limiting example of non-aerosol foamdispenser is disclosed in U.S. Pat. No. D456,260

It is explicitly understood that the pharmaceutical composition andmethods of the present invention are suitable for pharmacologicallyactive agents whether water soluble, poorly water soluble or waterinsoluble. The judicious choice of ingredients will allow the use of afoam delivery whether or not active ingredients are water soluble ornot. Combinations of active ingredients that are water soluble orinsoluble may also be practiced according to the present invention.There are many solutions to the problem of formulation of poorly solubleingredients for improved drug bioavailability including the use ofsurfactants, micelle solutions, emulsions, microemulsions and organiccosolvents, as are well known in the art of pharmaceutical formulations.

In some embodiments the pharmaceutically acceptable carrier is ahydrophilic carrier. In certain embodiments the composition of thepresent invention is an aqueous based foam. In some embodiments thecomposition comprises an oil-in-water emulsion, or microemulsion.

In other some embodiments the pharmaceutically acceptable carrier is alipophilic carrier. In certain embodiments the composition is alipid-based mousse. In some embodiments the composition comprises awater-in-oil emulsion. In certain embodiments the lipid is selected froma synthetic lipid, a semi-synthetic lipid and a natural lipid.

The composition of the present invention comprises a pharmaceuticalcarrier comprising at least one dispersing agent that is a foam formingagent. The dispersing agent may be selected form at least onepharmaceutically acceptable surfactant selected from anionic, cationic,nonionic, zwitterionic, amphoteric and ampholytic surfactants, as wellas mixtures of these surfactants. Nonlimiting examples of possiblesurfactants include polysorbates, such as polyoxyethylene (20) sorbitanmonostearate (polysorbate 60); Polyoxyethylene (20) sorbitan monolaurate(polysorbate 20); polyoxyethylene (20) sorbitan monooleate (polysorbate80); fatty acid esters, such as Myrj 45, Myrj 49 and Myrj 59;poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl ether,poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether,polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1;sucrose esters, partial esters of sorbitol and its anhydrides, such assorbitan monolaurate; mono or diglycerides, isoceteth-20, sodiummethylcocoyl taurate, sodium methyl oleoyl taurate, triethanolaminelauryl sulfate and betaines.

Other useful surfactants include alkali metal long-chain alkylsulfates,where the alkyl group has 9 to 15 carbon atoms, sodium lauryl sulfate(SLS), sodium dodecylbenzene sulfonate, sodium cocomonoglyceridesulfonate, sodium lauroylsarcosinate, and the like, potassium andtriethanolammonium sulfates, sulfonates and sarcosinates. Among thenonionic and amphoteric surfactants useful herein preferred are thoseselected from the group consisting of lauryl polyglucoside, decylpolyglucoside, coconut alkyl N-methyl glucose amide, oleyl betaine,cocamidopropyl betaine, cocamidopropyl hydroxysultaine, sodium laurylsarcosinate, coamdiopropyl PG-dimonium chloride phosphate, ceteth-2,ceteth-6, steareth-2, steareth-6, PEG-2 stearate, PPG-10 glycerylstearate, and mixtures thereof. More preferred are those selected fromthe group consisting of lauryl polyglucoside, decyl polyglucoside, oleylbetaine, cocamidopropyl betaine, cocamidopropyl hydroxysultaine, sodiumlauryl sarcosinate, coamdiopropyl PG-dimonium chloride phosphate andmixtures thereof.

The anionic surfactants advantageously employed in the composition ofthe present invention included poloxamers(poly(oxyethylene)-poly(oxypropylene) block copolymers).

Other foam forming agents include fatty alcohols having 12 or morecarbons in their carbon chain, such as cetyl alcohol and stearylalcohol, arachidyl alcohol, behenyl alcohol, 1-triacontanol, and fattyalcohols with longer carbon chains.

In certain embodiments of the present invention, the foam forming agentis a fatty acid having 16 or more carbons in its carbon chain, and isselected from hexadecanoic acid, stearic acid, arachidic acid, behenicacid, octacosanoic acid, and fatty acids having longer carbon chains ormixtures thereof.

In some embodiments of the present invention the foam forming agentcomprises a mixture of fatty alcohols, fatty acids and hydroxy fattyacids and derivatives thereof in any proportion.

In one currently preferred embodiment of the invention, thepharmaceutical composition of the present invention is administered tothe treated subject in a metered dose manner. The aerosol formulation ispreferably arranged so that each metered dose or “puff” of aerosol willejaculate a pre-determined volume of foam that would fill the ear canal.The advantage of the metered dose method is that the foam will not spillor reach beyond the ear canal, and a precise amount of the medicament isinserted.

In a preferred embodiment, an amount of about 0.1 cc to about 2.0 cc ofaerosol formulation is ejaculated per actuation. More preferably, anamount of about 0.2 to about 1 cc of aerosol formulation is ejaculatedper actuation of the device. The ejaculated amount is determinedaccording to the age of the treated subject, which affects the volume ofthe ear canal. For example, the ear canal volume of a newborn baby to aone-month old infant is usually around 0.2 cc, of a six month old infantis usually 0.5 cc and around 2.0 cc of children older than twenty-fourmonths and adults.

The use of metered dose devices for different applications is well knowin the art, and is described in details in U.S. Pat. Nos. 6,032,836;5,697,532; 5,502,076; 6,702,155; US Patent Application 20030178022, allincorporated herein by reference.

In a different embodiment, the delivery device of the foam-basedformulation of the invention may comprise two parts: one part serves asa container that stores the medicament formulation, and upon pressurethe medicament is ejected into the ear, in a metered dose manner in theform of foam. The second part is an extension or tube that leads thefoam toward the ear canal.

The subject, treated by the method of the present invention may be amammalian. In a preferred embodiment, the treated subject is a humanbeing. The method provided is applicable to any age and can be used tonewborns as well as adults. In a different embodiment the treatedsubject is an animal, preferably a domestic mammal, including but notlimited to household pets.

It is within the scope of the present invention, to use a pharmaceuticalcomposition in the form of a foam for the treatment of any ear disorderwhich requires administration of pharmaceutical composition through theexternal auditory meatus of a treated subject, so as to thereby treatthe subject. The ear disorder may include any of the abovementioneddisorders.

The present invention is further directed to a pharmaceuticalcomposition used for the treatment of ear disorder in a form of foam ormousse comprising as an active ingredient one or more antibiotic agent,antibacterial agent, antifungal agent, steroid agent, anti-inflammatoryagent, local anesthetic agent or a mixture thereof, together with apharmaceutically acceptable carrier.

Methods

The present invention also provides a process of preparing apharmaceutical composition for the treatment of an ear disorder in aform of foam or mousse to thereby treat a subject in need of suchtreatment comprising:

a. providing a pharmaceutical agent known to affect an ear disorder; and

b. admixing the pharmaceutical agent of step (a) together with apharmaceutically acceptable carrier comprising a dispersing agent thatis a foam forming agent;

c. introducing the mixture of (b) into a dispensing device.

According to one embodiment the dispensing device is a non-aerosoldispensing device. According other embodiments the dispensing devise isan aerosol device.

The pharmaceutically acceptable carrier includes an aqueous carrier, anon-aqueous carrier or a mixture thereof, including oil-in-wateremulsions ands water-in-oil emulsions.

The present invention further provides a method for treatment eardisorder in a subject in need of such treatment comprising:

a. providing a pharmaceutical agent known to affect an ear disorder;

b. admixing the pharmaceutical composition together with apharmaceutically acceptable carrier comprising a dispersing agent thatis a foam forming agent;

c. introducing the mixture in a container that enables the dispersion ofsaid mixture in a form of foam; and

d. administering the formulation of step (c) to the external auditorymeatus of said subject so as to thereby treat the subject.

In one embodiment of the invention, the pharmaceutical composition usedfor the treatment of ear disorder in the form of foam may comprise as anactive ingredient at least one pharmaceutical agent selected from anantibiotic agent, an antibacterial agent, an antifungal agent, a steroidagent, an anti-inflammatory agent, a local anesthetic agent or a mixturethereof, together with a pharmaceutically acceptable carrier. Thetreated disorder by the disclosed method may be any of theabovementioned disorders.

In some embodiments the pharmaceutically acceptable carrier is selectedfrom a hydrophilic carrier and a lipophilic carrier. In certainembodiments the pharmaceutically acceptable carrier further comprises alipid surfactant. According to various embodiments the lipid surfactantand said dispersion agent of step (b) are selected from the groupconsisting of cholesteryl esters, phospholipids, carbohydrates, andproteins.

The foam is administered preferably in a metered dose. Each metered doseformulation contains an acceptable therapeutic dosage and ejaculates toa final volume, which is suitable to fill the ear canal of the treatedsubject. In a further embodiment, the pharmaceutical composition is usedto manufacture a medicament.

During the production of the composition according to the presentinvention, a commonly used, a physiologically acceptable dispersionagent or stabilizer may be added. Non-limiting examples thereof include,propylene glycol, glycerine, polyethylene glycol, gelatin, dextran,polyvinylpyrrolidone, carboxymethyl cellulose, methyl cellulose,hydroxypropyl cellulose, sucrose fatty acid esters, polyoxyethylenehydrogenated castor oil, sterols, phospholipids, fatty acids, sugars,etc.

Furthermore the composition according to the present invention maycontain physiologically acceptable additives as desired. For example,acceptable additives include antioxidants, antiseptics, stabilizers,isotonizing agents, buffering agents, etc. The required and optimumamounts of these substances may be varied depending on the object.

The following is a non-limiting description of diseases and disordersthat may be amenable to treatment with the compositions and methods ofthe invention.

External Ear Disorders

The external ear is an area commonly subjected to acute and chronicinflammatory conditions. It consists of the auricle and externalauditory meatus. The auricle is primarily composed of fibroelasticcartilage to which the skin and a small portion of subcutaneous tissueare attached, and of fat in the lobule. The external auditory meatus(EAM) is a skin-lined canal approximately 2.5 cm in length and endsmedially at the tympanic membrane. Disorders of the outer ear includeblockages, infections (external otitis and perichondritis), eczema, andtumors. The outer ear is also prone to certain types of injury. TheMerck Manual, Second Home Edition, Chapter 219-220 Biology of the Ears,Nose, and Throat.

Blockages

Earwax (cerumen) may block the ear canal. Even large amounts of waxoften produce no symptoms. Symptoms can range from itching to a loss ofhearing. Other blockages can occur when people, particularly children,put foreign objects, such as beads, erasers, and beans, into the earcanal. Insects, particularly cockroaches, may also block the ear canal.

External Otitis

External otitis is infection of the ear canal. It may affect the entirecanal, as in generalized external otitis, or just one small area, as ina boil (furuncle) or pimple. A variety of bacteria or, rarely, fungi cancause generalized external otitis. Certain people, including those whohave allergies, psoriasis, eczema, or scalp dermatitis, are particularlyprone to external otitis. Injuring the ear canal while cleaning it orgetting water or irritants such as hair spray or hair dye in the canaloften leads to external otitis. External otitis is particularly commonafter swimming in fresh water pools, in which case it is sometimescalled “swimmer's ear”. Earplugs and hearing aids make external otitismore likely, particularly if these devices are not properly cleaned.

Acute otitis externa (AOE) affects four in every thousand Americansannually (Hannley M T, Denneny J C, Holzer S S. Use of ototopicalantibiotics in treating 3 common ear diseases. Otolaryngol Head NeckSurg 2000; 116:934-940), and is reported to be one of the leading causesof physician visits due to ear pain (LaRosa S. Primary Care Managementof otitis externa. Nurse Pract 1998; 23:125-133).

Some risk factors associated with AOE include living in tropical orhumid climates, summer season and swimmers or those who enjoy otherwater sports (Pelton S I, Klein J O. The draining ear. Otitis media andotitis externa. Infect Dis Clin North Am 1988; 2: 117-129; BiedlingmaierJ F. Two ear problems you may not need to refer. Postgrad Med 1994; 96:141-148). The warm and wet environment in the ear canal makes it anideal location for bacteria to inhabit and proliferate. Additional riskfactors as mentioned above, include insertion of foreign objects intothe ear canal, accumulation of cerumen (earwax), hearing aids, and someskin conditions (seborrhea, psoriasis, or eczema) (Biedlingmaier J F.ibid., 1994). Foreign objects such as cotton-tipped swabs or anythingused to clean the ear may damage and scratch the ear canal, making thearea susceptible to infection. The buildup of earwax and the use ofhearing aids may also decrease ventilation in the ear and keep the earcanal moist, thus leading to increased chances for developing AOE.Preventive measures to avoid the risk of AOE include keeping the earcanal clean and dry, using earplugs while swimming, avoiding cleaning orscratching ears with cotton-tipped swabs and avoiding shower heads withpowerful streams of water directed to the ear canal (LaRosa S. PrimaryCare Management of otitis externa. Nurse Pract 1998; 23:125-133).

The most commonly isolated pathogens are Pseudomonas aeruginosa andStaphylococcus aureus. Other pathogens less commonly cultured includeProteus mirabilis, Streptococci species, coagulase negativeStaphylococci, and various gram negative bacilli.

Symptoms of generalized external otitis are itching and pain. Sometimesan unpleasant-smelling white or yellow discharge drains from the ear.The ear canal may have no swelling, slight swelling, or in severe casesbe swollen completely closed. If the ear canal swells or fills with pusand debris, hearing is impaired. Usually, the canal is tender and hurtsif the external ear (pinna) is pulled or if pressure is placed on thefold of skin in front of the ear canal. To a doctor looking into the earcanal through an otoscope (a device for viewing the canal and eardrum),the skin of the canal appears red and swollen and may be littered withpus and debris.

The treatment of otitis externa involves frequent and through atraumaticcleansing of the canal, use of the appropriate topical antibiotics, andtreatment of associated inflammation and pain. Topical treatments havethe advantage of avoiding systemic side effects, enhancing patientcompliance, and maximizing treatment outcomes.

Chronic Otitis Externa

Chronic otitis externa (COE) is an inflammatory process of the ear canaldue to bacterial, fungal, or other dermatological disorders. COE canresult from recurrent otitis externa, chronic purulent otitis media withperforation, or eczematoid dermatitis. The disease can be defined byhaving persistent symptoms for more than 2 months, which includeunrelenting pruritus, mild discomfort, and dry flaky skin in the EAC.Multiagent topical treatments and frequent cleanings are oftennecessary. Topical application of steroids may help alleviate thechronic itching and resultant excoriations often present with thiscondition.

Otomycosis

Otomycosis is a fungal infection of the skin of the EAC. Fungi can beeither the primary pathogen or superimposed on bacterial infections. Themost common fungi implicated in otomycosis are Aspergillus and Candida.The usual symptoms of otomycosis are pruritis deep within the ear and anurge to scratch. Tinnitus is also a common presenting complaint.Treatment is directed at thorough cleaning and drying of the canalfollowed by the application of at least one topical antifungalmedication.

Granular Myringitis

Granular Myringitis is the result of localized chronic inflammation ofthe lateral surface of the pars tensa of the tympanic membrane and ischaracterized by persistent, incompletely epithelialized granulationtissue over the involved area. Gram-negative bacilli are the mostcommonly cultured organisms, especially Pseudomonas and Proteus species.Treatment includes careful and frequent debridement of the ear with theapplication of topical antibiotics, occasionally combined with steroids.

Perichondritis

Perichondritis is infection of the cartilage of the external ear.Injury, burns, insect bites, ear piercing, or a boil on the ear maycause perichondritis. The infection also tends to occur in people whoseimmune system is weakened and in people who have diabetes. The firstsymptoms are redness, pain, swelling of the ear, and sometimes a fever.Pus accumulates between the cartilage and the layer of connective tissuearound it (perichondrium). Sometimes the pus cuts off the blood supplyto the cartilage, destroying it and leading eventually to a deformedear. Although destructive and long-lasting, perichondritis tends toproduce only mild discomfort.

Bullous Myringitis

This is a viral infection often confined to the tympanic membrane andprimarily involves younger children. The presenting symptom is one ofsevere pain without fever and hearing loss. Treatment is aimed at painrelief and systemic and topical antibiotics to prevent secondarybacterial infection.

Tumors

Tumors of the ear may be noncancerous (benign) or cancerous (malignant).Noncancerous tumors may develop in the ear canal, blocking it andcausing hearing loss and a buildup of earwax. Such tumors include smallsacs filled with skin secretions (sebaceous cysts), osteomas (bonetumors), and growths of excess scar tissue after an injury (keloids).Basal cell and squamous cell cancers are common skin cancers that oftendevelop on the external ear after repeated and prolonged exposure to thesun. Ceruminoma (cancer of the cells that produce earwax) develops inthe outer third of the ear canal and can spread. Certainchemotherapeutic agents may be useful in treating or reducing thesymptoms associated with these disorders.

Injury

A number of different injuries can affect the outer ear. A blunt blow tothe external ear can cause bruising between the cartilage and the layerof connective tissue around it (perichondrium). When blood collects inthis area, the external ear becomes swollen and purple. The collectedblood (hematoma) can cut off the blood supply to the cartilage, allowingthat portion of the cartilage to die, leading in time to a deformed ear.This deformity, called a cauliflower ear, is common among wrestlers,boxers, and rugby players. A forceful blow to the jaw may fracture thebones surrounding the ear canal and distort the canal's shape, oftennarrowing it.

Middle and Inner Ear Disorders

Middle and inner ear disorders produce many of the same symptoms, and adisorder of the middle ear may affect the inner ear and vice versa.

Acute Otitis Media

Acute otitis media is a bacterial or viral infection of the middle ear.Acute otitis media results from infection by viruses or bacteria, oftenas a complication of the common cold or of allergies. Acute otitis mediais more common in children than in adults. The infected ear is painful,with a red, bulging eardrum. It is usually treated by antibiotics, suchas amoxicillin. Acetaminophen or nonsteroidal anti-inflammatory drugs(NSAIDs) can relieve pain. Decongestants containing phenylephrine mayhelp, and antihistamines are useful used for people who have allergies.

Occasionally acute otitis media is complicated with purulent dischargetypically via ventilation tubes (in the ear drum) or via perforation inthe ear drum, this condition is named suppurative otitis media which canbe acute or chronic. Presently, suppurative otitis media is treatedmainly with antibiotic ear drops.

Serous Otitis Media

Serous (secretory) otitis media is an accumulation of fluid in themiddle ear. It can develop from acute otitis media that has notcompletely cleared or from a blocked eustachian tube. Allergies are acommon cause of eustachian tube blockage. Serous otitis media can occurat any age but is particularly common in children.

Chronic Otitis

Chronic otitis media is a long-standing infection of the middle ear. Itis caused by a permanent hole (perforation) in the eardrum or anoncancerous growth of white skin like material (cholesteatoma). Peoplemay have a perforation without ever getting any symptoms, but sometimesa chronic bacterial infection develops. Chronic otitis media may flareup after an infection of the nose and throat, such as the common cold,or after water enters the middle ear while bathing or swimming. Usually,flare-ups result in a painless discharge of pus, which may bemalodorous, from the ear. Persistent flare-ups may result in theformation of protruding growths called polyps, which extend from themiddle ear through the perforation and into the ear canal. Persistentinfection can destroy parts of the ossicles, the small bones in themiddle ear that connect the eardrum to the inner ear and conduct soundsfrom the outer ear to the inner ear, causing conductive hearing loss.Other serious complications include inflammation of the inner ear,facial paralysis, and brain infections. Some people with chronic otitismedia develop cholesteatomas in the middle ear. Cholesteatomas, whichdestroy bone, greatly increase the likelihood of other seriouscomplications.

Mastoiditis

Mastoiditis is a bacterial infection in the mastoid process, theprominent bone behind the ear. This disorder usually occurs whenuntreated or inadequately treated acute otitis media spreads from themiddle ear into the surrounding bone, the mastoid process.

Perforation of the Eardrum

A perforation is a hole in the eardrum. A middle ear infection (otitismedia) is the most common cause of eardrum perforation. The eardrum canalso be perforated by a sudden change in pressure, either an increase,such as that caused by an explosion, a slap, or diving underwater, or adecrease, such as occurs while flying in an airplane. Another cause isburns from heat or chemicals. The eardrum may also be perforated(punctured) by objects placed in the ear, such as a cotton-tipped swab,or by objects entering the ear accidentally, such as a low-hanging twigor a thrown pencil. An object that penetrates the eardrum can dislocateor fracture the chain of small bones (ossicles) that connect the eardrumto the inner ear. Pieces of the broken ossicles or the object itself mayeven penetrate the inner ear. A blocked eustachian tube may lead to theperforation because of severe imbalance of pressure (barotrauma).Perforation of the eardrum causes sudden severe pain, sometimes followedby bleeding from the ear, hearing loss, and noise in the ear (tinnitus).The present invention further includes methods of treating thisdisorder.

Myringitis

Myringitis is infection of the eardrum caused by a variety of virusesand bacteria; the bacterium Mycoplasma is a common cause. The eardrumbecomes inflamed, and small, fluid-filled blisters (vesicles) form onits surface. Blisters may also be present in otitis media; however, inmyringitis, there is no pus or fluid in the middle ear.

Meniere's Disease

Meniere's disease is a disorder characterized by recurring attacks ofdisabling vertigo (a whirling sensation), hearing loss, and tinnitus.Meniere's disease is thought to be caused by an imbalance in the fluidthat is normally present in the inner ear. This fluid is continuallybeing secreted and reabsorbed, maintaining a constant amount. Either anincrease in production of inner ear fluid or a decrease in itsreabsorption results in an imbalance of fluid.

Temporal Bone Fracture

The temporal bone (the skull bone containing part of the ear canal, themiddle ear, and the inner ear) can be fractured by a blow to the head.Temporal bone fractures frequently rupture the eardrum and may alsodamage the ossicles and the cochlea. Symptoms include facial paralysison the side of the fracture and profound hearing loss, which may beconductive, sensorineural, or both.

Auditory Nerve Tumors

An auditory nerve tumor (acoustic neuroma, acoustic neurinoma,vestibular schwannoma, eighth nerve tumor) is a noncancerous (benign)tumor that originates in the cells that wrap around the auditory nerve(Schwann cells).

Barotrauma

Barotrauma is damage to the middle ear caused by unequal air pressure onthe two sides of the eardrum.

EXAMPLES

The following non-limiting examples of compositions in accordance withthe principles of the invention are provided for illustrative purposesonly.

Example 1 Analgesic Ear Foam

Table 1 provides a non-limiting example of a composition of the presentinvention for administration of an analgesic to the ear.

Preparation Method:

A) The components 03, 04, and 02 are dissolved in 07 in the stated orderin a stainless steel dissolving vessel of suitable capacity fitted witha propeller stirrer and turboemulsifier.B) 05, 06 and finally 01 are added while stirring, and theturboemulsifier is then operated for 15 minutes.C) Using a metering pump, the suspension is metered in the volumecorresponding to the theoretical weight into aerosol cans whilestirring.D) Each can is immediately sealed by clinching the dispenser valve andis then pressurized by means of the propellant, which is fed in underpressure in a suitable quantity by a pumping device.

TABLE 1 % COMPOSITION COMPONENT ACTIVITY (of pressurized liquid) 01antipyrin active principle 5 02 tetracaine active principle 0.5 03Potassium antioxidant 0.25 metabisulphite 04 Sodium antibacterial-anti-0.3 benzoate mildew agent 05 Polysorbate 20 foaming surfactant 4 06Polyglycol foam thickener 4 300 isostearate 07 Purified 75.87 water 08propellant 10

Example 2 Antibiotic Ear Foam

Foam compositions comprising at least one antibiotic agent are usefulfor the treatment of ear disorders indicating use of an antibiotic. Anon-limiting example of a composition comprising antibiotic agents ispresented in the table 2 herein below.

TABLE 2 % COMPOSITION (of pressurized COMPONENT ACTIVITY liquid) 01Neomycin active principles 5 Polymyxin B 10,000 units/ml Dexamethasone 102 Xanthan gum active principle 0.2 thickener and suspension agent 03Potassium active principle 0.25 metabisulphite antioxidant 04 EDTAbisodium active principle 0.3 salt antioxidant 05 Polysorbate 20 foamingsurfactant 4 06 Polyglycol 300 foam thickener 4 isostearate 07 Purifiedwater 75.25 08 propellant 6.5

Preparation Method:

A) The components 03, 04, and 02 are dissolved in 07 in the stated orderin a stainless steel dissolving vessel of suitable capacity fitted witha propeller stirrer and turboemulsifier.B) 05, 06 and finally 01 are added while stirring, and theturboemulsifier is then operated for 15 minutes.C) Using a metering pump, the suspension is metered in the volumecorresponding to the theoretical weight into aerosol cans whilestirring.D) Each can is immediately sealed by clinching the dispenser valve andis pressurized by means of the propellant, which is fed in underpressure in a suitable quantity by a pumping device

Example 3 Antibiotic Ear Foam 0.3% Ofloxacine

Table 3 provides an example of a composition of the present inventioncomprising a commonly administered antibiotic, ofloxacine.

TABLE 3 % COMPOSITION (of pressurized COMPONENT ACTIVITY liquid) 01Ofloxacine active principle 0.3 02 Dexamethasone active principle 1.0steroid 03 Polysorbate 20 foaming surfactant 4 04 Polyglycol 300 foamthickener 4 isostearate 05 Propyleneglycol 5 06 Purified water 75.7 07propellant 10

Preparation Method:

A) The components 01 and 02 are dissolved in 06 in the stated order in astainless steel dissolving vessel of suitable capacity fitted with apropeller stirrer and turboemulsifier.B) 03, 04, 05 and finally 01 are added while stirring, and theturboemulsifier is then operated for 15 minutes.C) Using a metering pump, the suspension is metered in the volumecorresponding to the theoretical weight into aerosol cans whilestirring.D) Each can is immediately sealed by clinching the dispenser valve andis then pressurized by means of the propellant, which is fed in underpressure in a suitable quantity by a pumping device.

Example 4 Lipid-Based Mousse Formulations

Lipid based formulations are particularly useful for use withoil-soluble therapeutic agents. Non-limiting examples of suchformulations are presented in table 4 herein below.

TABLE 4 Example Example Example Example 4A 4B 4C 4D Petrolatum 10-20%10-20% 10-20% 10-20% Neomycin 5% Polymyxin B 10,000 u/ml Dexamethasone1%  1%  1% Tetracaine  0.5% Antipyrine  5% ciprofloxacine  0.2%ofloxacine  0.3% Alkyl 10%   10%  10%  10% benzoate Sorbitan 2.5-4.5%2.5-4.5% 2.5-4.5% 2.5-4.5% Stearate Polysorbate 2.3-5.7% 2.3-5.7%2.3-5.7% 2.3-5.7% 60 Water 20-75% 20-75% 20-75% 20-75% propellant 5%  5% 5%  5% Total 100%  100% 100% 100%

It will be appreciated by a person skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed hereinabove. Rather, the scope of the invention is defined bythe claims that follow.

1. A pharmaceutical composition in a form of a foam or mousse for thetreatment of an ear disorder comprising: a) at least one pharmaceuticalagent known to affect an ear disorder; and b) a pharmaceuticallyacceptable carrier comprising at least one dispersing agent that is afoam forming agent; wherein the agent of a) and the agent of b) packedin a dispensing device adapted for the dispensing the agent of a)admixed with the agent of b) to the ear canal in a form of a foam or amousse.
 2. The pharmaceutical composition according to claim 1, whereinthe dispersing agent is selected from the group consisting of asurfactant, a cholesteryl ester, a fatty acid, a phospholipid, acarbohydrate and a protein.
 3. The pharmaceutical composition accordingto claim 1, wherein the dispensing device is selected from the groupconsisting of an aerosol dispensing device and a non-aerosol dispensingdevice.
 4. The pharmaceutical composition according to claim 1, whereinthe pharmaceutical agent is selected from the group consisting of anantibiotic agent, an antibacterial agent, an antifungal agent, a steroidagent, an anti-inflammatory agent, a local anesthetic agent and amixture thereof.
 5. The pharmaceutical composition according to claim 1,wherein the antibiotic agent is selected from the group consisting ofamikacin, gentamycin, tobramycin, streptomycin, netilmycin, kanamycinciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin,levofloxacin, enoxacin, sulfonamides, polymyxin, chloramphenicol,neomycin, paramomomycin, colistimethate, bacitracin, vancomycin,tetracyclines, rifampins, cycloserine, beta-lactams, cephalosporins, andpharmaceutically acceptable derivatives thereof.
 6. The pharmaceuticalcomposition according to claim 1, wherein the steroid agent is selectedfrom the group consisting of betamethasone, betamethasone dipropionate,fluocinonide, fluocinoline acetonide, hydrocortisone,methylprednisolone, clobetasol, beclomethasone, dexamethasone sodiumphosphate, triamcinolone and pharmaceutically acceptable derivativesthereof.
 7. A method of preparing a pharmaceutical composition for thetreatment of an ear disorder in the form of a foam or mousse, the methodcomprising the steps of: a. providing a pharmaceutical agent known toaffect an ear disorder; b. admixing the pharmaceutical agent of step (a)with a suitable pharmaceutically acceptable carrier comprising adispersing agent that is a foam forming agent; c. introducing themixture of (b) into a dispensing device adapted for the dispensing thecomposition to the external auditory meatus in the form of a foam ormousse.
 8. The method according to claim 7, wherein the dispersing agentis selected from the group consisting of a surfactant, a cholesterylester, a fatty acid, a phospholipid, a carbohydrate and a protein. 9.The method according to claim 7, wherein the dispensing device isselected from the group consisting of an aerosol dispensing device and anon-aerosol dispensing device.
 10. A method for the treatment of an eardisorder in a subject in need of such treatment, the method comprisingthe step of administering into the ear canal of the subject apharmaceutical agent known to affect an ear disorder, the pharmaceuticalagent being administered in the form of a foam or mousse.
 11. The methodaccording to claim 10, wherein the pharmaceutical agent is selected fromthe group consisting of an antibiotic agent, an antibacterial agent, anantifungal agent, a steroid agent, an anti-inflammatory agent, a localanesthetic agent and a mixture thereof.
 12. The method according toclaim 11, wherein the antibiotic agent is selected from the groupconsisting of amikacin, gentamycin, tobramycin, streptomycin,netilmycin, kanamycin ciprofloxacin, norfloxacin, ofloxacin,trovafloxacin, lomefloxacin, levofloxacin, enoxacin, sulfonamides,polymyxin, chloramphenicol, neomycin, paramomomycin, colistimethate,bacitracin, vancomycin, tetracyclines, rifampins, cycloserine,beta-lactams, cephalosporins, and pharmaceutically acceptablederivatives thereof.
 13. The method according to claim 11, wherein thesteroid agent is selected from the group consisting of betamethasone,betamethasone dipropionate, fluocinonide, fluocinoline acetonide,hydrocortisone, methylprednisolone, clobetasol, beclomethasone,dexamethasone sodium phosphate, triamcinolone and pharmaceuticallyacceptable derivatives thereof.
 14. The method according to claim 10,wherein the ear disorder is selected from an external ear disorder, amiddle ear disorder and an inner ear disorder.
 15. The method accordingto claim 10, wherein the ear disorder is acute otitis externa orotalgia.
 16. The method according to claim 10, wherein the administeringstep is accomplished by ejecting the foam or mousse into the ear canalfrom a dispensing device.
 17. A dispensing device for dispensing apharmaceutical composition to the ear, comprising: a containercontaining a pharmaceutical agent known to affect an ear disorder, insuch a manner that, when the pharmaceutical composition is dispensedfrom the container, it is dispensed in the form of a foam or mousse; anda pipe that extends at a right angle from the container and that allowsaccess of the foam or mousse to the ear.
 18. The dispensing device inaccordance with claim 17, wherein the pharmaceutical composition ispacked in the container under pressure.